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Multicenter Study
. 2024 Nov 1;142(11):1081-1086.
doi: 10.1001/jamaophthalmol.2024.3836.

Biallelic Loss-of-Function Variants in UBAP1L and Nonsyndromic Retinal Dystrophies

Ehsan Ullah  1 , Siying Lin  2   3 , Jiaxiong Lu  4   5 , Chelsea Bender  1 , Andrew R Webster  2   3 , Samantha Malka  2   3 , Savita Madhusudhan  6   7 , Emma Rees  8 , Denise Williams  8 , Aime R Agather  1 , Catherine A Cukras  1 , Robert B Hufnagel  1   9 , Rui Chen  4   5 , Laryssa A Huryn  1 , Gavin Arno  2   3   10 , Bin Guan  1
Affiliations
Multicenter Study

Biallelic Loss-of-Function Variants in UBAP1L and Nonsyndromic Retinal Dystrophies

Ehsan Ullah et al. JAMA Ophthalmol. .

Abstract

Importance: Inherited retinal dystrophies (IRDs) present a challenge in clinical diagnostics due to their pronounced genetic heterogeneity. Despite advances in next-generation sequencing (NGS) technologies, a substantial portion of the genetic basis underlying IRDs remains elusive. Addressing this gap seems important for gaining insights into the genetic landscape of IRDs, which may help improve diagnosis and prognosis and develop targeted therapies in the future.

Objective: To provide a clinical and molecular characterization of 6 patients with IRDs with biallelic disease-causing variants in a novel candidate IRD disease gene.

Design, setting, and participants: This multicenter case series study included 6 patients with IRDs from 4 tertiary hospitals (in the US: National Eye Institute, National Institutes of Health Clinical Center; in the UK: Moorfields Eye Hospital, Royal Liverpool University Hospital, Birmingham Women's and Children's).

Exposures: Biallelic disease-causing variants in the novel candidate IRD disease gene, UBAP1L.

Main outcome and measures: Participants underwent comprehensive clinical ophthalmic assessments to characterize the features of retinal dystrophy. Exome and genome sequencing revealed candidate variants in the UBAP1L gene; no other plausible disease variants in known IRD genes were identified. A minigene assay provided functional insights for a noncanonical splice variant, and a knockout mouse model was used for in vivo functional elucidation.

Results: Four homozygous UBAP1L variants were identified in the affected individuals from 6 families, including 2 frameshift variants (c.710del and c.634_644del), 1 canonical splice variant (c.121-2A>C), and 1 noncanonical splice variant (c.910-7G>A), which was shown to cause aberrant splicing and frameshift in a minigene assay. Participants presented with retinal dystrophy including maculopathy, cone dystrophy, and cone-rod dystrophy. Single-cell RNA sequencing of the retina showed that human UBAP1L is highly expressed in both cones and retinal pigment epithelium, whereas mouse Ubap1l is highly expressed in cone cells only. Mice with truncation of the C-terminal SOUBA domain did not manifest retinal degeneration up to 15 months of age.

Conclusions and relevance: Study results reveal clinical and genetic evidence that loss of UBAP1L function was associated with inherited retinopathy in humans. These findings hold promise for improved clinical diagnostics, prognosis, and the potential development of targeted therapies for individuals affected by IRDs.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cukras reported being an employee of Hoffman-La Roche outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Pedigrees Affected by Retinal Dystrophy With Variants in the UBAP1L Gene
The genotypes of tested individuals are listed. Blue-filled symbols represent individuals diagnosed with retinal dystrophy and probands. m1, c.121-2A>C; m2, c.634_644del; m3, c.710del; m4, c.910-7G>A. Numbers next to symbols indicate numbers of individuals.
Figure 2.
Figure 2.. Ophthalmological Imaging of Participants 1 and 2
Top, color fundus photographs of the right and left eye for participant 1 (A) and pseudocolor fundus photographs of the right and left eye for participant 2 (B). Bottom, fundus autofluorescence and optical coherence tomography images of the right and left eye for participant 1 and participant 2.
See this image and copyright information in PMC

References

    1. Duncan JL, Pierce EA, Laster AM, et al. ; and the Foundation Fighting Blindness Scientific Advisory Board . Inherited retinal degenerations: current landscape and knowledge gaps. Transl Vis Sci Technol. 2018;7(4):6. doi: 10.1167/tvst.7.4.6 - DOI - PMC - PubMed
    1. Carss KJ, Arno G, Erwood M, et al. ; NIHR-BioResource Rare Diseases Consortium . Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease. Am J Hum Genet. 2017;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003 - DOI - PMC - PubMed
    1. Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010;29(5):335-375. doi: 10.1016/j.preteyeres.2010.03.004 - DOI - PubMed
    1. Chiang JP, Trzupek K. The current status of molecular diagnosis of inherited retinal dystrophies. Curr Opin Ophthalmol. 2015;26(5):346-351. doi: 10.1097/ICU.0000000000000185 - DOI - PubMed
    1. RetNet . Retinal Information Network home page. Accessed April 15, 2024. https://sph.uth.edu/retnet/

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